Retinoic Acid Enhances Foxp3 Induction Indirectly by Relieving Inhibition from CD4+CD44hi Cells

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2008 Nov 14

PMID 19006694

Citations 196

Authors

Jonathan A Hill

Jason A Hall

Cheng-Ming Sun

Qi Cai

Norbert Ghyselinck

Pierre Chambon

Yasmine Belkaid

Diane Mathis

Christophe Benoist

Affiliations

Soon will be listed here.

Abstract

CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA.

Citing Articles

Maintenance DNA methylation is required for induced regulatory T cell reparative function following viral pneumonia.

Joudi A, Gurkan J, Liu Q, Acosta M, Helmin K, Morales-Nebreda L bioRxiv. 2025; .

PMID: 40060513 PMC: 11888461. DOI: 10.1101/2025.02.25.640199.

Retinoic Acid (RA): A Critical Immunoregulatory Molecule in Asthma and Allergies.

Lotfi R Immun Inflamm Dis. 2024; 12(10):e70051.

PMID: 39466149 PMC: 11514501. DOI: 10.1002/iid3.70051.

The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes.

Esposito M, Amory J, Kang Y J Exp Med. 2024; 221(9).

PMID: 39133222 PMC: 11318670. DOI: 10.1084/jem.20240519.

Distal Immunization and Systemic Cytokines Establish a Transient Immune Alert State in the Intestine.

Wu Y, Huang J, Conlon M, Shenoy M, Chao J, Chooi M J Immunol. 2024; 213(3):373-383.

PMID: 38884660 PMC: 11250722. DOI: 10.4049/jimmunol.2400209.

Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis.

Zhang J, Liu H, Chen Y, Liu H, Zhang S, Yin G Front Immunol. 2024; 15:1312919.

PMID: 38322264 PMC: 10844451. DOI: 10.3389/fimmu.2024.1312919.

References

Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan A, Stroud J . FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006; 126(2):375-87. DOI: 10.1016/j.cell.2006.05.042. View

Apostolou I, von Boehmer H . In vivo instruction of suppressor commitment in naive T cells. J Exp Med. 2004; 199(10):1401-8. PMC: 2211808. DOI: 10.1084/jem.20040249. View

Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z . Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006; 212:8-27. DOI: 10.1111/j.0105-2896.2006.00427.x. View

Kang S, Lim H, Andrisani O, Broxmeyer H, Kim C . Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol. 2007; 179(6):3724-33. DOI: 10.4049/jimmunol.179.6.3724. View

Huehn J, Siegmund K, Lehmann J, Siewert C, Haubold U, Feuerer M . Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med. 2004; 199(3):303-13. PMC: 2211798. DOI: 10.1084/jem.20031562. View

Chapellier B, Mark M, Garnier J, Dierich A, Chambon P, Ghyselinck N . A conditional floxed (loxP-flanked) allele for the retinoic acid receptor gamma (RARgamma) gene. Genesis. 2002; 32(2):95-8. DOI: 10.1002/gene.10072. View

Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N . Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003; 198(12):1875-86. PMC: 2194145. DOI: 10.1084/jem.20030152. View

Elias K, Laurence A, Davidson T, Stephens G, Kanno Y, Shevach E . Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood. 2007; 111(3):1013-20. PMC: 2214761. DOI: 10.1182/blood-2007-06-096438. View

Nicholson R, Mader S, Nagpal S, Leid M, Rochette-Egly C, Chambon P . Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO J. 1990; 9(13):4443-54. PMC: 552237. DOI: 10.1002/j.1460-2075.1990.tb07895.x. View

10.

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

11.

Veldhoen M, Hocking R, Atkins C, Locksley R, Stockinger B . TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24(2):179-89. DOI: 10.1016/j.immuni.2006.01.001. View

12.

Fantini M, Becker C, Monteleone G, Pallone F, Galle P, Neurath M . Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004; 172(9):5149-53. DOI: 10.4049/jimmunol.172.9.5149. View

13.

Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig M, von Boehmer H . Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005; 6(12):1219-27. DOI: 10.1038/ni1265. View

14.

Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille J, Curotto de Lafaille M . Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest. 2005; 115(7):1923-33. PMC: 1142115. DOI: 10.1172/JCI24487. View

15.

Rodrigo Mora J, Iwata M, Eksteen B, Song S, Junt T, Senman B . Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science. 2006; 314(5802):1157-60. DOI: 10.1126/science.1132742. View

16.

Schambach F, Schupp M, Lazar M, Reiner S . Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol. 2007; 37(9):2396-9. DOI: 10.1002/eji.200737621. View

17.

Reich M, Liefeld T, Gould J, Lerner J, Tamayo P, Mesirov J . GenePattern 2.0. Nat Genet. 2006; 38(5):500-1. DOI: 10.1038/ng0506-500. View

18.

Abb J, Abb H, Deinhardt F . Effect of retinoic acid on the spontaneous and interferon-induced activity of human natural killer cells. Int J Cancer. 1982; 30(3):307-10. DOI: 10.1002/ijc.2910300309. View

19.

Yamagata T, Mathis D, Benoist C . Self-reactivity in thymic double-positive cells commits cells to a CD8 alpha alpha lineage with characteristics of innate immune cells. Nat Immunol. 2004; 5(6):597-605. DOI: 10.1038/ni1070. View

20.

Hsieh C, Zheng Y, Liang Y, Fontenot J, Rudensky A . An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol. 2006; 7(4):401-10. DOI: 10.1038/ni1318. View